therapy to oral sildenafil in severe
idiopathic pulmonary arterial hypertension
Zeynep Pınar ÖNEN, Öznur AKKOCA YILDIZ, Banu ERİŞ GÜLBAY, Gülseren KARABIYIKOĞLU
Ankara Üniversitesi Tıp Fakültesi, Göğüs Hastalıkları Anabilim Dalı, Ankara.
ÖZET
Ağır idiyopatik pulmoner arteryel hipertansiyonda oral sildenafil tedavisine eklenen inhale iloprost te- davisinin uzun dönem sonuçları
İdiyopatik pulmoner arteryel hipertansiyon (İPAH) oldukça nadir görülen ve tedavi edilmediğinde hızlı bir seyirle sağ kalp yetmezliği ve ölüme kadar giden morbidite ve mortalitesi yüksek bir hastalıktır. Son yıllarda tedavi alanındaki gelişmeler- le hastalığın seyri değiştirilebilmektedir. Ancak alternatif tedavi protokollerinin uzun dönem sonuçları ve hastaların bu te- davilere olan yanıtları ile ilgili yeterli veri bulunmamaktadır. Daha önce geçici olarak konvansiyonel tedavi ve oral kalsi- yum blokerine yanıt veren İPAH olgusunda sildenafil monoterapisinin uzun dönem klinik ve fizyolojik etkilerini, inhale sil- denafil tedavisi eklenmesi sonrasındaki değişikliklerle karşılaştırdık. İPAH olgularında vazodilatör tedavilere kısa süreli ve geçici yanıtlar verilebilmektedir. Ancak uzun dönem sonuçları ile ilgili yeterli veri olmayıp, mutlaka takip edilmelidirler ve bu hastalarda kombinasyon tedavileri daha etkili olabilmektedir.
Anahtar Kelimeler:İdiyopatik pulmoner arteryel hipertansiyon, sildenafil, inhale iloprost, kombinasyon tedavisi, uzun dö- nem tedavi.
SUMMARY
Inhaled iloprost as a long-term additional therapy to oral sildenafil in severe idiopathic pulmonary arterial hypertension
Zeynep Pınar ÖNEN, Öznur AKKOCA YILDIZ, Banu ERİŞ GÜLBAY, Gülseren KARABIYIKOĞLU
Department of Chest Disease, Faculty of Medicine, Ankara University, Ankara, Turkey.
Yazışma Adresi (Address for Correspondence):
Dr. Zeynep Pınar ÖNEN, Ankara Üniversitesi Tıp Fakültesi, Göğüs Hastalıkları Anabilim Dalı, Cebeci Hastanesi, Dikimevi, ANKARA - TURKEY
e-mail: zponen@yahoo.com
Idiopathic pulmonary arterial hypertension (IPAH) is an uncommon disease (with an annu- al incidence of 1 to 2 per million) which causes severe limitations on exercise capacity, with an increase in pulmonary vascular resistance and leading to right ventricular failure (1,2). Altho- ugh IPAH is a progressive disease with high mor- tality, the recent outcomes are heterogeneous, with some patients dying within months of diag- nosis and others living for decades. The course of the disease has also been altered by advances in medical therapies (3).
Conventional treatment, including warfarin, di- uretics, digoxin respectively; improved survival in retrospective and prospective studies, used to reduce the fluid overload state for hemodynamic optimization, used in right ventricular dysfuncti- on but the long term benefit is uncertain (4-6).
To reduce potential component of hypoxic vaso- constriction home oxygen therapy is recom- mended. Furthermore, chronic administration of oral calcium channel blockers (CCB) is benefici- al in less than 10% of IPAH patients and real res- ponders have high rates of tolerance in long- term follow up (5,7).
Phosphodiesterases are a super family of enzy- mes that inactivate cyclic adenosine monop- hosphate and cyclic guanosine monophosphate, which are the second messengers of prostacyc- lin and nitric oxide. Phosphodiesterases also ha- ve different tissue distributions and substrate af- finities and phosphodiesterase-5 is abundantly expressed in lung tissue (8,9). Sildenafil is a se- lective vasodilator that enhances and prolongs
(a primary mediator of vasodilatation) with se- lective inhibition of the cyclic guanosine monop- hosphate specific phosphodiesterase-5 isoenzy- me (10).
Inhalation of iloprost, a stable prostacyclin ana- logue, causes pulmonary vasodilatation matc- hed to ventilation but avoids vasodilatation in non ventilated lung areas. Long-term use of in- haled iloprost has been shown to improve exer- cise capacity and hemodynamic variables in pa- tients with IPAH (11).
We reported a case of IPAH who respectively be- nefited from long-term conventional therapy plus oral sildenafil monotherapy and additional inhaled iloprost therapy for 18 months.
CASE REPORT
A fourty-one years old male patient was admit- ted to our hospital with the diagnosis of IPAH. He had previous three years for ruling out collagen vascular disease, pulmonary disease and/or pulmonary thromboembolic disease, left heart abnormality and other systemic disorders by;
blood tests, pulmonary function tests, perfusion lung scan, pulmonary high resolution CT, Dopp- ler echocardiography and right-left heart cathe- terization respectively as defined by World He- alth Organization World Symposium on pulmo- nary hypertension. Afterwards he had received long-term conventional therapy plus oral calci- um channel antagonist. At the time of diagnosis, echocardiographic systolic pulmonary arterial pressure (sPAP) was 95 mmHg, after 1 year tre- atment sPAP decreased to 65 mmHg, which is Idiopathic pulmonary arterial hypertension (IPAH) is an uncommon and devastating disease which, if untreated, progresses rapidly and leads to right heart failure and death. The course of the disease has been altered by advances in medical therapi- es. However, the effects of long-term alternative therapies and responses to each treatment protocols are not definite. We want to define an IPAH case, which had long-term temporary responses to the conventional therapy plus calcium channel blockers treatment and moreover compared the long-term clinical and physiologic effects of oral sildenafil mono therapy and additional inhaled iloprost therapy. Patients with IPAH may have response to a short-term vasodilatation therapy but they have to fol- low for the long-term results and may be of benefit from combination treatments.
Key Words:Idiopathic pulmonary arterial hypertension, sildenafil, inhaled iloprost, combination treatment, long-term tre- atment.
however in the second and third year due to cli- nical and hemodynamic deterioration he rece- ived too much oral calcium channel antagonist because of the initial response but just side ef- fects were reported instead of improvement. At the admission to our clinics, right heart failure signs were manifest; dyspnea and fatigue were also present in any physical activity, New York Heart Association (NYHA) functional class was IV. Echocardiographic sPAP was 125 mmHg and the other baseline data is shown in Table 1.
Systemic mean arterial blood pressure was me- asured and a six minute walking test (6MWT) with modified Borg dyspnea scale was perfor- med before and after sildenafil monotherapy. Al- so we tried to perform symptom limited cardi- opulmonary exercise testing but the patient co- uld not complete the test. After patient gave written informed consent, a 100 mg/day oral do- se of sildenafil was given additionally to the war- farin and diuretic treatment. Medication was well tolerated without any side effect and the patient continued to receive same dose. After two we- eks he reported an improvement in dyspnea on exertion and at the 3rdmonth 20% decrease was reported in sPAP without significant changes in systemic blood pressure. Besides, NYHA functi- onal class improved from IV to II with an arterial oxygen increase, six-minute walk distance (6MWD) increased from 302 meters to 580 me- ters and Borg dyspnea index reduced from 8 to 1 after 6MWT. At the 6thmonth controls, altho-
ugh the sPAP was stable, exercise dyspnea dete- riorated and 6MWD decreased from 580 m to 440 m with leg discomfort and fatigue. Additi- onally NYHA functional class increased from II to III (Table 1). Because of this condition and ac- cording to guidelines patient received additional inhaled iloprost 100 µg/day with 6 inhalations per day. The conventional treatment and oral sil- denafil regimen were unchanged. Also every measurement were repeated as same as silde- nafil monotherapy protocol (Table 1). Flushing was the only side effect during combination tre- atment. After six months of combination therapy NYHA functional class reduced from III to I and stable at the 12th month also sPAP is reduced 36% from the baseline sPAP and 48% at the 6th and 12th month, respectively. 6MWD increased from 302 m to 600 m. Symptom-limited cardi- opulmonary exercise testing was performed successfully at the 6th and 12thmonth, VO2pe- ak were 1.05 L/min and 1.20 L/min respecti- vely, the increase was 15% (Table 1). Patient has still receiving combination therapy and ongoing his usual life.
DISCUSSION
We want to define an IPAH case, which had long- term temporary response to the conventional therapy plus CCB treatment and compared the long-term clinical and physiologic effects of oral sildenafil monotherapy and additional inhaled iloprost therapy.
Table 1. Patient data during treatment protocols.
NYHA/ Systemic Borg Symptom limited
WHO sPAP 6MWD mean arterial SaO2 dyspnea cardiopulmonary Class (mmHg) (m) blood pressure ( % ) exercise testing
Baseline (admission) IV 125 302 70 86 8 Not completed
Sildenafil 100 mg/d 3rdmonth II 100 580 85 91 1
Sildenafil 100 mg/d 6thmonth III 100 440 80 88 6
Sildenafil 100 mg/d + Inh. I 80 580 75 92 0.5 VO2 peak= 1.05 L/min
Iloprost 100 µg/d 6th month Peak work= 140 watt
SaO2 peak= 86%
Sildenafil 100 mg/d + Inh. I 65 600 75 92 0 VO2 peak= 1.20 L/min
Iloprost 100 µg/d 12th month Peak work= 160 watt
SaO2 peak= 86%
Chronic administration of CCB is beneficial who demonstrate acute vasoreactivity. Patient with true vasoreactive response, demonstrate a re- duction in the mean PAP more than 10 mmHg to reach lower than 40 mmHg in the absence of decrease in systemic arterial pressure. Our pati- ent was responder at the first year but in time course received CCB for another two years and deteriorated. In the IPAH treatment, common opinion with the patients who initially respond to CCB therapy but subsequently develop disease progression should be treated with alternative agents and calcium channel blocker should be discontinued (12). Because of this agreement we decided to change the treatment protocol.
Histological microthrombosis of the small ves- sels is often seen with IPAH. Likely benefit from anticoagulation in IPAH is related to the effect on the in-situ thrombosis and possibly occurs by counteracting the effects of thrombin activation and associated with prolonged survival in IPAH (4). Diuretics prevent sodium and water retenti- on and have great impact on physical capacity and quality of life in many patients. Also remain the gold standard for relieving the symptoms of fluid overload in right heart failure (6). In 1993 Ogata et al. reported the five year survival was significantly higher in the group treated with an- ticoagulants and vasodilators (13). There was no contraindication for the conventional therapy so we prefer to continue warfarin and diuretics in our patient.
Sildenafil is a recently developed vasodilator and a specific inhibitor of phosphodiesterase-5.
So far there are only small numbers of reports about long-term treatment with sildenafil mo- notherapy. In our case, medication doses were well tolerated without any side effect. Also the 6MWD, Borg dyspnea index, echocardiographic sPAP improved at the second week of treatment and maintained at the 3rdmonth but symptoms and functional clinical status changed at the 6th month of mono therapy. Bharani and associates treated 10 patient with sildenafil after two weeks the 6MWT and dyspnea index significantly imp- roved, with a decrease in echocardiographic sPAP levels (14). Ghofrani and colleagues found
sildenafil caused strong dose dependent pulmo- nary vasodilatation, even in the absence of exo- genous nitric oxide administration in patients with PAH as early as in the second week and re- mained at the 3rd month (15). In these studies acute effects were seen in the second week as we reported and the long term treatment time was three months but we treated our patient with sildenafil monotherapy for six months and the results at the 3rdand 6thmonths were not simi- lar. We did not prefer to increase the treatment doses because sildenafil is a systemic drug so side effects can be occur dose dependently. Al- so our patient had a transient response to anot- her vasodilator for long-term treatment; we pre- ferred to add another vasodilator to the sildena- fil treatment.
Addition of inhaled iloprost to the long-term the- rapy with sildenafil monotherapy improved Borg dyspnea index, 6MWD, NYHA functional class, sPAP without significant decrease in systemic mean arterial blood pressure and oxygen satura- tion at the reported doses. This improvement was similar with the 3rdmonth sildenafil monot- herapy results and also the results were mainta- ined at the 6thand the 12th month with combi- nation therapy. Wilkens and Ghofrani reported additional improvement with combination the- rapy but the results were just for three months ti- me (7,16).
There are a range of non-invasive and invasive parameters used to monitor disease progressi- on in IPAH. Worsening the exercise dyspnea is the most obvious and probably most sensitive marker of the underlying disease progression associated with IPAH, NYHA functional class has proven to be the most practical parameter which shows the clinical status of affected pati- ents, 6MWT can also be combined with that from commonly used Borg dyspnea index a self measure of perceived breathlessness (17). The echocardiogram is an important non-invasive tool both in terms of diagnosis and prognosis in IPAH (18). That’s why we preferred to diagnose and monitor our patient with Doppler echocar- diography, NYHA functional class and six-minu- te walk test with Borg dyspnea index. These
have been used to demonstrate the responses to each treatment successfully and objectively in our case.
Idiopathic pulmonary arterial hypertension is characterized by extensive remodeling of the pulmonary vasculature. During the last decade some advances in the treatment have been ac- hieved. However, the appropriate therapies are limited because of poor efficacy or high costs.
Potentially new treatment options such as oral sildenafil offer patients effective therapies. On the other hand response to the treatment may be transient because of this remodeling and ne- ed appropriate follow up time to decide the tre- atment protocols require additional therapies. In conclusion, combination treatments seems to allow to reverse remodeling and entire disease process better than monotherapy but still there is not enough long-term outcomes with combi- nation therapies.
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